CN113307811B - Tetrahydropyranyl amino-pyrrolopyrimidinones and methods of use thereof - Google Patents

Tetrahydropyranyl amino-pyrrolopyrimidinones and methods of use thereof Download PDF

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CN113307811B
CN113307811B CN202110663289.5A CN202110663289A CN113307811B CN 113307811 B CN113307811 B CN 113307811B CN 202110663289 A CN202110663289 A CN 202110663289A CN 113307811 B CN113307811 B CN 113307811B
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cancer
btk
compound
compounds
carcinoma
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CN113307811A (en
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J-M.拉皮埃尔
S.伊蒂拉
N.纳姆德夫
B.施瓦茨
太田悠介
百瀬孝幸
常深智之
稲垣裕章
中山清
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Arqule Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Abstract

The present application relates to tetrahydropyranyl amino-pyrrolopyrimidinones and methods of use thereof. The present application relates to compounds of formula (I):

Description

Tetrahydropyranyl amino-pyrrolopyrimidinones and methods of use thereof
The application relates to a split application of a Chinese patent application 201580085832.0 'tetrahydropyranyl amino-pyrrolopyrimidinone and a using method thereof', wherein the application date of the split application is 2015, 12, 23.
Technical Field
The present application relates to inhibitors of Bruton's Tyrosine Kinase (BTK), including mutant BTK, useful in the treatment of diseases or conditions associated with BTK kinase, including immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction and neurological disorders. In particular, the present application relates to BTK inhibiting compounds and compositions thereof, methods of treating BTK-related diseases or disorders, and methods of synthesizing these compounds.
Background
BTK is a member of the Tec family of tyrosine kinases and plays an important role in regulating early B cell development and mature B cell activation and survival. (Hunter, cell,1987 50, 823-829). Downstream of various receptors (e.g., growth factors, B cell antigens, chemokines, and innate immune receptors), BTK triggers numerous cellular processes including cell proliferation, survival, differentiation, motility, angiogenesis, cytokine production, and antigen presentation.
The BTK deficient mouse model has shown a role for BTK in allergic disorders and/or autoimmune diseases and/or inflammatory diseases. For example, BTK deficiency in standard murine preclinical models of Systemic Lupus Erythematosus (SLE) has been shown to lead to significant improvement in disease progression. In addition, BTK deficient mice are resistant to developing collagen-induced arthritis and are less susceptible to staphylococcal-induced arthritis. Due to the role of BTK in B cell activation, BTK inhibitors can also be used as inhibitors of B cell mediated pathogenic activities (e.g., autoantibody production). The expression of BTK in osteoclasts, mast cells and monocytes has been shown to be important for the function of these cells. For example, impaired IgE-mediated mast cell activation and reduced TNF- α production by activated monocytes has been associated with BTK deficiency in mice and humans. Thus, BTK inhibition is useful in the treatment of allergic disorders and/or autoimmune and/or inflammatory diseases, such as SLE, rheumatoid arthritis, polyangiitis, idiopathic Thrombocytopenic Purpura (ITP), myasthenia gravis, allergic rhinitis and asthma (DiPaolo et al, nature chem. Biol.2011,7 (1): 41-50; liu et al, journal. Pharmacol. And exp. Ther.2011, 338 (1): 154-163).
Furthermore, the role of BTK in apoptosis demonstrates the utility of inhibition of BTK activity for the treatment of cancer, B-cell lymphomas, leukemias and other hematological malignancies. In addition, given the role of BTK in osteoclast function, inhibition of BTK activity can be used to treat bone diseases such as osteoporosis.
Thus, inhibition of BTK using small molecule inhibitors has potential as a treatment for immune disorders, cancer, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction and neurological disorders. Thus, there remains a significant need for effective small molecule inhibitors of BTK.
Disclosure of Invention
A first aspect of the application relates to compounds of formula (I):
or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analogue or derivative thereof. As used herein, the expressions "compound of formula (I)" and "compound (I)" refer to the same compound and are used interchangeably.
Another aspect of the application relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, and a pharmaceutically acceptable diluent, excipient or carrier.
Another aspect of the application relates to a method of treating a BTK-mediated disorder. The method comprises administering to a patient in need of treatment of a disease or disorder associated with BTK kinase modulation a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof.
Another aspect of the application relates to a method of treating a BTK-mediated disorder. The method comprises administering to a patient in need of treatment of a disease or disorder associated with BTK kinase modulation a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, and a pharmaceutically acceptable diluent, excipient or carrier.
Another aspect of the application relates to a method of treating a cell proliferative disorder. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof.
Another aspect of the application relates to a method of treating a cell proliferative disorder. The method comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, and a pharmaceutically acceptable diluent, excipient or carrier.
Another aspect of the application relates to a method of treating cancer. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof.
Another aspect of the application relates to a method of treating cancer. The method comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, and a pharmaceutically acceptable diluent, excipient or carrier.
Another aspect of the application relates to methods of modulating (e.g., inhibiting) BTK. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof.
Another aspect of the application relates to methods of modulating (e.g., inhibiting) BTK. The method comprises administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, and a pharmaceutically acceptable diluent, excipient or carrier.
Another aspect of the application relates to a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, for use in a method of treating a BTK-mediated disorder, a cell proliferative disorder or cancer, or modulating (e.g. inhibiting) BTK. A compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, is administered to a patient in need thereof in a therapeutically effective amount.
Another aspect of the application relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, and a pharmaceutically acceptable diluent, excipient or carrier, for use in a method of treating a BTK-mediated disorder, cell proliferative disorder or cancer, or modulating (e.g. inhibiting) BTK. The composition is administered to a patient in need thereof in a therapeutically effective amount.
Another aspect of the application relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof in the manufacture of a medicament for the treatment of a BTK mediated disorder, a cell proliferative disorder or cancer, or for modulating (e.g. inhibiting) BTK. A compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, is administered to a patient in need thereof in a therapeutically effective amount.
Another aspect of the application relates to the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, and a pharmaceutically acceptable diluent, excipient or carrier, in the manufacture of a medicament for the treatment of a BTK-mediated disorder, cell proliferative disorder or cancer, or for modulating (e.g. inhibiting) BTK. The composition is administered to a patient in need thereof in a therapeutically effective amount.
The application also provides methods of treating diseases or conditions associated with modulation of BTK kinase, including but not limited to immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine function disorders, and neurological disorders, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog, or derivative thereof, to a patient suffering from at least one of the diseases or conditions.
The present application provides inhibitors of BTK that are therapeutic agents in the treatment of diseases such as immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine function disorders, neurological disorders, and other diseases associated with the modulation of BTK kinase.
The present application also provides compounds and compositions having improved potency and safety characteristics relative to known BTK inhibitors. The application also provides agents having novel mechanisms of action for BTK kinases in the treatment of various types of diseases including immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolism/endocrine function disorders and neurological disorders. Finally, the present application provides a medical community with novel pharmacological strategies for the treatment of diseases and conditions associated with BTK kinase.
Detailed description of the preferred embodiments
The present application relates to compounds and compositions capable of modulating the activity of Bruton's Tyrosine Kinase (BTK). The application features methods of treating, preventing, or alleviating a disease or condition in which BTK plays a role by administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog, or derivative thereof. The methods of the application can be used to treat a variety of BTK-mediated diseases and conditions by inhibiting the activity of BTK kinase. Inhibition of BTK provides treatment, prevention, or alleviation of diseases including, but not limited to, immune disorders, cancer, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders, and neurological disorders.
In a first aspect of the application, compounds of formula (I) are described:
and pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof.
In one embodiment, the compound of formula (I) is a pharmaceutically acceptable salt. In another embodiment, the compound of formula (I) is a hydrate. In yet another embodiment, the compound of formula (I) is a solvate.
The details of the application are set forth in the following description. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, the exemplary methods and materials are now described. Other features, objects, and advantages of the application will be apparent from the description and from the claims. In the specification and the claims which follow, the singular form will also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. All patents and publications cited in this specification are incorporated herein by reference in their entirety.
Definition of the definition
The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.
The term "and/or" is used in this disclosure to mean either "and" or "unless otherwise indicated.
The application also includes pharmaceutical compositions comprising an effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier.
As used herein, the term "carrier" encompasses carriers, excipients and diluents and refers to materials, compositions or vehicles, such as liquid or solid fillers, diluents, excipients, solvents or encapsulating materials, that participate in carrying or transporting an agent from one organ or portion of a subject's body to another organ or portion of its body.
The compounds of formula (I) may form salts, which are also within the scope of the present application. Unless otherwise indicated, references to compounds of the formulae described herein should be understood to include references to salts thereof.
Representative "pharmaceutically acceptable salts" include, for example, water soluble and water insoluble salts, such as acetate, an Suo acid salts (4, 4-diaminostilbene-2, 2-disulfonate), benzenesulfonate, benzoate, hydrogencarbonate, hydrogensulfate, hydrogentartrate, borate, bromide, butyrate, calcium edetate, dextromethorphanate (camsylate), carbonate, chloride, citrate, clavulanate (clavuliarate), dihydrochloride, edetate, ethanedisulfonate, etoate, ethanesulfonate, fumarate, fiunarate, glucoheptonate, gluconate, glutamate, glycolyl para-aminophenylarsonate (glycinate), hexafluorophosphate, hexylresorcinol salt (hexylesporinate), hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothiosulfate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, muciate, naphthalenesulfonate, nitrate, N-methylhydroxylamine, 3-hydroxy-2-palminate, 1-hydroxy-1-naphthalene, 3-hydroxy-1-hydroxy-napthalate, ebergate (einbonate)), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate (suramate), tannate, tartrate, chlorate, tosylate, triethyliodide, and valerate.
The compounds of the application, for example, including pharmaceutically acceptable salts, tautomers, prodrugs and polymorphs of the compounds, may exist in solvated or unsolvated forms along with other solvent molecules.
"solvate" means a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds or salts have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alkoxide. The hydrate retains its H by one or more molecules of water and water therein 2 A combination of molecular species in the O molecular state.
All stereoisomers (e.g., geometric isomers, optical isomers, etc.) of the compounds of the application (including those of the salts, solvates, esters and prodrugs of the compounds and of the prodrugs), such as those attributable to asymmetric carbons at various substituents, including enantiomeric forms (which may even exist in the absence of an asymmetric carbon), rotameric forms, atropisomers and diastereoisomeric forms are included within the scope of the application as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). For example, if the compound of formula (I) contains a double bond or a fused ring, both cis and trans forms, as well as mixtures are contemplated as being within the scope of the present application. The individual stereoisomers of the compounds of the application may, for example, be substantially free of other isomers, or may, for example, be mixed as racemates or with all other, or other selected stereoisomers. The chiral centers of the present application may have either the S or R configuration as defined by IUPAC 1974 reconfigurations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like is intended to apply equally to the salts, solvates, esters and prodrugs of the enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the compounds of the application.
The term "isomer" refers to compounds having the same composition and molecular weight but different physical and/or chemical properties. The structural differences may be in the construction (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the compounds of formula (I) may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures or as individual enantiomers or diastereomers.
In this specification, for convenience in some cases, the structural formula of a compound represents a certain isomer, but the present application includes all isomers, such as geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers, and the like.
"isomerism" means that compounds have the same molecular formula but differ in the order in which their atoms are bonded or in the arrangement of their atoms in space. Isomers whose atoms are arranged differently in space are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers" and stereoisomers that are non-superimposable mirror images of each other are referred to as "enantiomers" or sometimes as optical isomers. Mixtures containing equal amounts of individual enantiomeric forms with opposite chirality are referred to as "racemic mixtures".
The compounds of the application may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the application, and mixtures thereof, including racemic mixtures, are intended to form part of the present application. In addition, the present application encompasses all geometric and positional isomers. For example, if the compounds of the present application include double bonds or fused rings, both cis and trans forms as well as mixtures are contemplated as falling within the scope of the present application. Each compound disclosed herein includes all enantiomers conforming to the general structure of the compound. The compounds may be in racemic or enantiomerically pure form, or in any other form in terms of stereochemistry. The analysis results may reflect data collected for racemic forms, enantiomerically pure forms, or any other form in terms of stereochemistry.
The carbon atoms to which the four different substituents are bonded are referred to as "chiral centers".
"chiral isomer" means a compound having at least one chiral center. Compounds having more than one chiral center may exist as a single diastereomer or as a mixture of diastereomers (referred to as a diastereomeric mixture). When a chiral center is present, stereoisomers may be characterized by the absolute configuration of the chiral center (R or S). Absolute configuration refers to the arrangement in space of substituents attached to the chiral center. Substituents attached to the chiral center under consideration are arranged according to the order rules (Sequence Rule) of Cahn, ingold and Prelog (Cahn et al, angew.chem.Inter.edit.1966,5, 385; error Table 511; cahn et al, angew.chem.1966, 78, 413; cahn and Ingold, J.chem.Soc.1951 (London), 612; cahn et al, experientia 1956, 12, 81; cahn, J.chem.Educ.1964, 41, 116).
"geometric isomers" means diastereomers whose presence is due to a hindered rotation about a double bond. These configurations are distinguished in their name by the prefix cis and trans or Z and E, which means that the radicals are on the same side or on opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rule.
In another embodiment of the application, the compound of formula (I) is an enantiomer. In some embodiments, the compound is the (S) -enantiomer. In other embodiments, the compound is the (R) -enantiomer. In other embodiments, the compound of formula (I) may be the (+) or (-) enantiomer. The compounds may contain more than one stereocenter.
In another embodiment of the application, the compound of formula (I) is a diastereomer. In some embodiments, the compound is a cis diastereomer. In other embodiments, the compound is a trans diastereomer.
Based on their physicochemical differences, the diastereomeric mixture may be separated into its individual diastereomers by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers may be separated by: the enantiomeric mixture is converted to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher acid chloride), the diastereomers are separated, and the individual diastereomers are converted (e.g., hydrolyzed) to the corresponding pure enantiomers. Enantiomers can also be separated by using chiral HPLC columns.
It is also possible that the compounds of the present application may exist in different tautomeric forms and all such forms are contemplated as falling within the scope of the present application. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the present application.
A "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This conversion results in a formal transfer of the hydrogen atom, accompanied by a conversion of the adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric series in solution. In solid form, one tautomer is usually predominant. In solutions where tautomerization may exist, chemical equilibrium of the tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that can be converted into each other by tautomerization is called tautomerism.
Of the various types of tautomerism that are possible, two are generally observed. In keto-enol tautomerism, simultaneous migration of electrons and hydrogen atoms occurs. Ring-chain tautomerism occurs as a result of the reaction of an aldehyde group (-CHO) in a sugar chain molecule with one of the hydroxyl groups (-OH) in the same molecule, giving it a cyclic (ring-shaped) form as exhibited by glucose.
Common tautomeric pairs are: keto-enols, amide-nitriles, lactam-lactams, amide-imidic acid tautomerism in heterocycles (e.g. in bases such as guanine, thymine and cytosine), amine-enamines and enamine-imines. Included in the present application are (pyrrolopyrimidinyl) methanone- (pyrrolopyrimidinyl) methanol tautomeric pairs:
the present application relates to compounds of formula (I) or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof, which are capable of inhibiting BTK and are useful in the treatment of diseases and conditions associated with the modulation of BTK kinase. The application also relates to compounds of formula (I), or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof, which are useful for inhibiting BTK. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK.
Another aspect of the application relates to compounds of formula (I), wherein the compounds inhibit kinase activity of mutant BTKs, e.g., resistant mutant BTKs comprising a resistant mutation (e.g., a C481S mutation). In some embodiments, the patient or subject does not respond to the BTK inhibitor or relapse after BTK inhibitor treatment due to mutations (e.g., C481S mutations) that prevent targeted inhibition of BTK kinase. In one embodiment, the BTK mutation is a C481S mutation.
In some embodiments, the present application provides compounds of formula (I), wherein the compounds are more potent in inhibiting BTK activity than one or more known BTK inhibitors, including, but not limited to, ibrutinib, GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774, and LFM-A13. For example, the compound may be ibrutinib, GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774 and/or LFM-A13 efficiency in inhibiting BTK activity (e.g., by IC 50 Measured) at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold.
In some embodiments, the application provides compounds of formula (I), wherein the compounds are more potent in inhibiting the activity of BTK comprising one or more mutations as described herein (e.g., C481S) than one or more known BTK inhibitors (including, but not limited to, ibrutinib, GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774, and LFM-A13). For example, the compound may be at least about 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold, or about 100-fold more potent than ibrutinib, GDC-0834, RN486, CGI-560, CGI-1746, HM-71224, CC-292, ONO-4059, CNX-774, and/or LFM-a13 (e.g., as measured by IC 50) in inhibiting the activity of BTK containing one or more mutations as described herein. The resistant BTK mutant may have a resistant mutation comprising a C481S mutation without limitation.
Can pass through IC 50 Values are used to determine the efficacy of the inhibitor. IC as determined under substantially similar conditions 50 Lower value compounds relative to IC 50 Higher value compounds are more potent inhibitors.
The compounds of the application may be converted to N by treatment with an oxidizing agent, such as 3-chloroperoxybenzoic acid (m-CPBA) and/or hydrogen peroxideOxides to provide other compounds of the application. Accordingly, all nitrogen-containing compounds shown and claimed are considered to include the compounds shown and their N-oxide derivatives (which may be represented as N.fwdarw.O or N + -O - ) Both of which are located in the same plane. In addition, in other cases, nitrogen in the compounds of the present application may be converted to N-hydroxy or N-alkoxy compounds. For example, the N-hydroxy compound may be prepared by oxidation of the parent amine with an oxidizing agent (e.g., m-CPBA). All nitrogen-containing compounds shown and claimed are also considered to cover the compounds shown and their N-hydroxy (i.e., N-OH) and N-alkoxy (i.e., N-OR, where R is a substituted OR unsubstituted C, when valence and structure permit 1 -C 6 Alkyl, C 1 -C 6 Alkenyl, C 1 -C 6 Alkynyl, 3-14-membered carbocyclic or 3-14-membered heterocyclic) derivatives.
As used herein, the term "prodrug" means a compound that can be converted in vivo to the disclosed compound by metabolic means (e.g., by hydrolysis).
Because prodrugs are known to enhance numerous desirable properties of drugs (e.g., solubility, bioavailability, preparation, etc.), the compounds of formula (I), or pharmaceutically acceptable salts, tautomers, solvates, metabolites, polymorphs, analogs, or derivatives thereof, may be delivered in prodrug form. Accordingly, the present application is intended to cover prodrugs of compounds of formula (I), or pharmaceutically acceptable salts, tautomers, solvates, metabolites, polymorphs, analogs, or derivatives thereof, methods of delivering the prodrugs, and compositions containing the prodrugs. "prodrugs" are intended to include any covalently bonded carriers that release the active parent drug of the present application in vivo when such prodrugs are administered to a mammalian subject. Prodrugs are prepared by modifying functional groups present in the compound in such a way that the modification cleaves to the parent compound either in routine manipulation or in vivo. Prodrugs include compounds of the application wherein a hydroxyl group or an amino group is bonded to any group that, when the prodrug of the application is administered to a mammalian subject, cleaves to form a free hydroxyl group or a free amino group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the formulae described herein or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs, or derivatives thereof.
The term "crystalline polymorph", "polymorph" or "crystalline form" refers to a crystalline structure in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to a crystalline form predominance. Crystalline polymorphs of a compound can be prepared by crystallization under different conditions.
As used herein, the term "analog" refers to the following compounds: which is similar in structure to another compound but slightly different in composition (e.g., one atom is replaced by an atom of a different element or a specific functional group is present, or one functional group is replaced by another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound, but differs in structure or origin.
The present application also includes isotopically-labeled compounds, which are identical to those recited in the formulae described herein, but for the fact that one or more atoms are replaced by an atom having an atomic weight or mass number different from the atomic weight or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the application include isotopes of hydrogen, carbon, nitrogen, fluorine, for example 3 H、 11 C、 14 C、 2 H and 18 F。
compounds of formula (I) containing the aforementioned isotopes and/or other isotopes of other atoms, or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogues or derivatives thereof, are within the scope of the present application. Isotopically-labeled compounds of the present applicationObjects, e.g. incorporating radioactive isotopes therein, e.g 3 H、 14 Those of C may be used in drug and/or basal tissue distribution assays. Tritiated (i.e., 3 h) And carbon-14 (i.e., 14 c) Isotopes are useful to make them easy to prepare and detectable. 11 C and C 18 The F isotope can be used for PET (positron emission tomography). PET can be used for brain imaging. In addition, heavier isotopes such as deuterium are used (i.e., 2 h) Substitution may provide certain therapeutic advantages resulting from higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some cases. Isotopically-labeled compounds of formula (I), or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs, or derivatives thereof, can be prepared by generally performing the procedures disclosed in the schemes and/or examples herein by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof is not isotopically labeled.
The present application relates to compounds that are modulators of BTK. In one embodiment, the compounds of the application are inhibitors of BTK.
The term "administering" as used herein refers to administering a disclosed compound or a pharmaceutically acceptable salt or composition of a disclosed compound directly to a subject, or administering a prodrug, derivative or analog of the compound or a pharmaceutically acceptable salt or composition of the compound to a subject, which forms an equivalent amount of the active compound in the subject.
A "patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.
An "effective amount" or "therapeutically effective amount" when used in combination with a compound or pharmaceutical composition is an amount effective for treating or preventing a disease in a subject as described herein.
The term "treating" with respect to a subject refers to ameliorating at least one symptom of a disorder in the subject. Treatment includes curing, ameliorating or at least partially alleviating the condition.
The compounds of the application, or pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs or derivatives thereof, are also useful for preventing diseases, conditions or disorders. As used herein, "preventing" describes reducing or eliminating the onset of symptoms or complications of a disease, condition, or disorder.
The term "disorder" is used herein to mean and be used interchangeably with the term disease, condition, or disorder, unless otherwise indicated.
As used herein, the term "BTK-mediated" disease or condition refers to any disease or other detrimental condition in which BTK or a mutant thereof is known to play a role. Thus, another embodiment of the application relates to treating or lessening the severity of one or more diseases in which BTK or a mutant thereof is known to act. In particular, the present application relates to a method of treating, or lessening the severity of, a disease or disorder selected from a proliferative disorder or an autoimmune disorder, wherein said method comprises administering to a patient in need thereof a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, or a composition according to the application.
As used herein, the term "cell proliferative disorder" refers to a condition in which unregulated or abnormal growth of cells, or both, can lead to the development of an unwanted condition or disease, which can be cancerous or non-cancerous. Exemplary cell proliferative disorders of the application include various conditions in which cell division is unregulated. Exemplary cell proliferative disorders include, but are not limited to, neoplasms, benign tumors, malignant tumors, pre-cancerous conditions, in situ tumors, encapsulated tumors (encapsulated tumor), metastatic tumors, liquid tumors, solid tumors, immunological tumors, hematological tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells. The term "rapidly dividing cells" as used herein is defined as any cells that divide at a rate that exceeds or is greater than that expected or observed in adjacent or juxtaposed cells within the same tissue. Cell proliferative disorders include precancerous or precancerous conditions. Cell proliferative disorders include cancer. Preferably, the methods provided herein are used to treat or alleviate symptoms of cancer. The term "cancer" includes solid tumors, hematological tumors and/or malignant tumors. A "pre-cancerous cell" or "precancerous cell" is a cell that exhibits a cell proliferative disorder that is a pre-cancerous or precancerous condition. A "cancer cell" or "cancerous cell" is a cell that exhibits a cell proliferative disorder that is cancer. Any reproducible measurement means can be used to identify cancer cells or pre-cancerous cells. Cancer cells or pre-cancerous cells can be identified by histological classification or grading of a tissue sample (e.g., a biopsy sample). Cancer cells or precancerous cells can be identified by the use of suitable molecular markers.
Exemplary non-cancerous conditions or disorders include, but are not limited to, rheumatoid arthritis, inflammation, autoimmune diseases, lymphoproliferative conditions, acromegaly, rheumatoid spondylitis, osteoarthritis, gout, other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pneumonia, inflammatory bowel disease, crohn's disease, psoriasis, eczema, ulcerative colitis, pancreatic fibrosis, liver fibrosis, acute and chronic kidney disease, irritable bowel syndrome, pyresis, restenosis, cerebral malaria, stroke and ischemic injury, neurotrauma, alzheimer's disease, huntington's disease, parkinson's disease, acute and chronic pain, allergic rhinitis, allergic conjunctivitis, chronic heart failure, acute syndrome, cachexia, malaria, leprosy, leishmaniasis, lyme disease, leigh-synovitis, muscle degeneration, bursitis, tendinitis, tenosynovitis, herniated disc, disc rupture or herniated disc syndrome, bone sclerosis, thrombosis, restenosis, silicosis, pulmonary sarcoidosis, bone resorption diseases such as osteoporosis, graft versus host reaction, multiple sclerosis, lupus, fibromyalgia, AIDS and other viral diseases such as shingles, herpes simplex type I or II, influenza virus and cytomegalovirus, and diabetes.
Exemplary cancers include, but are not limited to, but are not limited to, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphomas, anal cancers, anal rectal cancers, anal canal cancers, appendicular cancers, childhood cerebellar astrocytomas, childhood cerebral astrocytomas, basal cell cancers, skin cancers (non-melanoma), biliary cancers, extrahepatic bile duct cancers, intrahepatic bile duct cancers, bladder cancers (loader cancer), bladder cancers (urinary bladder cancer), bone and joint cancers, osteosarcoma and malignant fibrous histiocytomas, brain cancers, brain stem gliomas, cerebellar astrocytomas, brain astrocytomas/malignant gliomas, ependymomas, medulloblastomas, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic gliomas, breast cancers, bronchial adenomas/carcinoids, carcinoid tumors, gastrointestinal, nervous system cancers nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative diseases, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasm, mycosis fungoides, szerni Syndrome (Seziary Syndrome), endometrial cancer esophageal cancer, extracranial blastoma, extragonadal blastoma, extrahepatic cholangiocarcinoma, ocular cancer, intraocular melanoma, retinoblastoma, gallbladder cancer, stomach (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), blastoma, ovarian blastoma, gestational trophoblastoma glioma, head and neck cancer, hepatocellular (liver) cancer, hodgkin lymphoma, hypopharyngeal cancer, and, intraocular melanoma, eye cancer, islet cell tumor (endocrine pancreas), kaposi's sarcoma, renal cancer (kidney cancer), renal cancer (renal cancer), renal cancer (kidney cancer), laryngeal cancer, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, lip and mouth cancer, liver cancer, lung cancer, non-small cell lung cancer, AIDS-related lymphoma, non-Hodgkin's lymphoma, primary central nervous system lymphoma, waldensted giant globulinemia, myeloblastoma, melanoma, intraocular (ocular) melanoma, meckel cell carcinoma, malignant mesothelioma, metastatic squamous neck cancer, mouth cancer (mouth cancer), tongue cancer, multiple endocrinopathy syndrome mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative diseases, chronic myelogenous leukemia, acute myelogenous leukemia, multiple myeloma, chronic myeloproliferative disease, nasopharyngeal carcinoma, neuroblastoma, oral carcinoma (oral cancer) (oral cavity cancer), oropharyngeal carcinoma, ovarian epithelial carcinoma, ovarian low malignancy potential, pancreatic carcinoma, pancreatic islet cell pancreatic carcinoma, paranasal sinus and nasal carcinoma, parathyroid carcinoma, penile carcinoma, pharyngeal carcinoma, pheochromocytoma, pineal tumor and supratentorial neuroectodermal tumor, pituitary tumor, plasmacytoid neoplasm/multiple myeloma, pleural lung blastoma, prostate carcinoma, rectal carcinoma, renal pelvis and ureter, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland carcinoma, ewing family of sarcoma tumors, kaposi's sarcoma, soft tissue sarcoma, uterine carcinoma, uterine sarcoma, skin carcinoma (non-melanoma), skin carcinoma (melanoma), meeker cell skin carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (stomach) carcinoma, supratentorial primitive neuroectodermal tumors, testicular cancer, laryngeal carcinoma, thymoma and thymus carcinoma, thyroid carcinoma, transitional cell carcinoma of the renal pelvis and ureter and other urinary organs, gestational trophoblastic tumors, urinary tract carcinoma, endometrial carcinoma, uterine sarcoma, uterine body carcinoma, vaginal carcinoma, vulval carcinoma and Wilms' tumor.
Process for preparing compounds
The compounds of the present application may be prepared by a variety of methods, including standard chemical methods. Suitable synthetic routes are depicted in the schemes presented below.
The compounds of formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups are employed for sensitive or reactive groups where necessary according to general principles or chemistry. The protecting groups were manipulated according to standard methods of organic synthesis (T.W.Greene and P.G.M.Wuts, "Protective Groups in Organic Synthesis", third edition, wiley, new York 1999). These groups are removed at a convenient stage of the compound synthesis using methods readily apparent to those skilled in the art. The method of choice as well as the reaction conditions and order of execution thereof should be consistent with the preparation of the compounds of the present application.
One skilled in the art will recognize whether a stereocenter is present in the compound of formula (I). Thus, the present application includes both possible stereoisomers (unless specifically indicated in the synthesis) and includes not only the racemic compounds, but also individual enantiomers and/or diastereomers. When the desired compound is a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate, or starting material may be effected by any suitable method known in the art. See, e.g., E.L.Eliel, S.H.Wilen, and L.N.Mander, "Stereochemistry of Organic Compounds" (Wiley-lnterscience, 1994).
The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic and/or enzymatic methods.
The compounds of the present application may be prepared by a number of methods well known to those skilled in the art of organic synthesis. By way of example, the compounds of the present application may be synthesized using the methods described below as well as synthetic methods known in the art of synthetic organic chemistry, or variations of the above methods as understood by those skilled in the art. Preferred methods include, but are not limited to, those described below. The compounds of the present application (i.e., compounds of formula (I)) can be synthesized by following the procedure outlined in general scheme 1, which includes combining the sequences of intermediates 2-a to 2-h. The starting materials are either commercially available or are prepared by known procedures in the reported literature or as exemplified.
General scheme 1
General procedure for the preparation of compounds of formula (I) by using intermediates 2-a, 2-b, 2-c, 2-d, 2-e, 2-f, 2-g and 2-h is outlined in scheme 1. Nucleophilic addition of phenol 2-b to 2-chloro-4-fluorobenzonitrile 2-a using a strong base, such as sodium hydride (NaH), in a solvent, such as N, N-Dimethylformamide (DMF), yields 2-c. Hydrolysis of 2-c using a base, such as potassium hydroxide (KOH), in a solvent, such as ethanol, at elevated temperature produces carboxylic acid 2-d. Using a base (e.g. potassium carbonate (K) 2 CO 3 ) Or cesium carbonate (Cs) 2 CO 3 ) Esterification of 2-d with methyl iodide in a solvent, such as N, N-Dimethylformamide (DMF), provides 2-e. Acylation of intermediate 2-f with 2-e using a strong base, such as n-butyllithium (n-BuLi), in a solvent, such as Tetrahydrofuran (THF), provides 2-g. Nucleophilic addition of amine 2-h to aryl chloride 2-g using a base, such as N, N-Diisopropylethylamine (DIPEA), and optionally in a solvent, such as N, N-Dimethylformamide (DMF), provides compounds of formula (I).
Depending on the nature of the separation, the enantiomers, diastereomers, cis/trans mixtures resulting from the above methods can be separated into their individual components by chiral salt techniques, chromatography using normal, reverse phase or chiral columns.
Bioassays
Determination of BTK kinase Activity
Test inhibitors and controls were prepared in solvent (i.e., DMSO) and added to each well of the reaction plate. Full length active BTK was diluted in assay buffer and added to each well. After pre-incubation, the kinase reaction is initiated by adding an activating mixture diluted in assay buffer containing biotinylated plcγ2 peptide and ATP. Wen Yoban and subsequently stopping the reaction in the dark by adding a stop/detect mixture prepared in the assay buffer. The assay plate was incubated in the dark and read on a plate reader.
Determination of BTK C481S kinase Activity
Test inhibitors and controls were prepared in solvent (i.e., DMSO) at the desired final concentration and added to each well of the reaction plate. Full length BTKC481S was diluted in assay buffer and added to each well in a volume. After pre-incubation, the kinase reaction is initiated by adding an activating mixture diluted in assay buffer containing biotinylated plcγ2 peptide and ATP. Wen Yoban and subsequently stopping the reaction in the dark by adding a stop/detect mixture prepared in the assay buffer. The assay plate was incubated in the dark and read on a plate reader.
Antiproliferative assays
Cell viability was determined by the MTS assay. Briefly, cells (i.e., TMD-8 cells or Rec-1 cells) were plated in 96-well plates, cultured in complete growth medium, and subsequently treated with various drugs and drug combinations. MTS/PMS was added and incubated, followed by assessment of cell viability using a microplate reader. Data were normalized to untreated controls and analyzed with Microsoft Excel.
Methods of using compounds
Another aspect of the application relates to methods of treating, preventing, inhibiting or eliminating diseases or conditions associated with BTK modulation (e.g., inhibition of BTK). The method comprises administering to a patient in need of treatment of a disease or disorder associated with BTK modulation an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, or a pharmaceutical composition of a compound of formula (I). In one embodiment, the BTK-mediated disorder is selected from the group consisting of an immune disorder, cancer, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction, and neurological disorder. In some embodiments, the method further comprises administering an additional therapeutic agent selected from the group consisting of an anti-inflammatory agent, an immunomodulator, a chemotherapeutic agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, an agent for treating a hematological disorder, an agent for treating diabetes, and an agent for treating an immunodeficiency disorder. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK (e.g., BTK C481S mutant).
Another aspect of the application relates to a method of treating, preventing, inhibiting or eliminating a cell proliferative disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, or a pharmaceutical composition of the compound of formula (I). In one embodiment, the cell proliferative disorder is cancer. In some embodiments, the method further comprises administering an additional therapeutic agent selected from the group consisting of an anti-inflammatory agent, an immunomodulator, a chemotherapeutic agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, an agent for treating a hematological disorder, an agent for treating diabetes, and an agent for treating an immunodeficiency disorder.
Another aspect of the application relates to a method of modulating BTK comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, or a pharmaceutical composition of a compound of formula (I). In one embodiment, modulating BTK is inhibiting BTK. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK (e.g., BTK C481S mutant).
Another aspect of the application relates to a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, for use in a method of treating a BTK mediated disorder. In one embodiment, the disease or condition is selected from the group consisting of immune disorders, cancer, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction, and neurological disorders. In some embodiments, the method further comprises administering an additional therapeutic agent selected from the group consisting of an anti-inflammatory agent, an immunomodulator, a chemotherapeutic agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, an agent for treating a hematological disorder, an agent for treating diabetes, and an agent for treating an immunodeficiency disorder. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK (e.g., BTK C481S mutant).
In another aspect, the application relates to a pharmaceutical composition of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, for use in a method of treating a BTK mediated disorder. In one embodiment, the disease or condition is selected from the group consisting of immune disorders, cancer, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction, and neurological disorders. In some embodiments, the method further comprises administering an additional therapeutic agent selected from the group consisting of an anti-inflammatory agent, an immunomodulator, a chemotherapeutic agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, an agent for treating a hematological disorder, an agent for treating diabetes, and an agent for treating an immunodeficiency disorder. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK (e.g., BTK C481S mutant).
Another aspect of the application relates to a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, for use in a method of treating, preventing, inhibiting or eliminating a cell proliferative disorder. In one embodiment, the cell proliferative disorder is cancer.
In another aspect, the present application relates to a pharmaceutical composition of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, for use in a method of treating, preventing, inhibiting or eliminating a cell proliferative disorder. In one embodiment, the cell proliferative disorder is cancer.
Another aspect of the application relates to a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, for use in modulating BTK. In one embodiment, modulating BTK is inhibiting BTK. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK (e.g., BTK C481S mutant).
In another aspect, the application relates to a pharmaceutical composition of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, for use in modulating BTK. In one embodiment, modulating BTK is inhibiting BTK. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK (e.g., BTK C481S mutant).
Another aspect of the application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, in the manufacture of a medicament for the treatment of a BTK mediated disease or condition. In one embodiment, the disease or condition is selected from the group consisting of immune disorders, cancer, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction, and neurological disorders. In some embodiments, the treatment further comprises administering an additional therapeutic agent selected from the group consisting of an anti-inflammatory agent, an immunomodulator, a chemotherapeutic agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, an agent for treating a hematological disorder, an agent for treating diabetes, and an agent for treating an immunodeficiency disorder. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK (e.g., BTK C481S mutant).
In another aspect, the application relates to the use of a pharmaceutical composition of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, in the manufacture of a medicament for the treatment of a BTK mediated disease or condition. In one embodiment, the disease or condition is selected from the group consisting of immune disorders, cancer, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction, and neurological disorders. In some embodiments, the treatment further comprises administering an additional therapeutic agent selected from the group consisting of an anti-inflammatory agent, an immunomodulator, a chemotherapeutic agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, an agent for treating a hematological disorder, an agent for treating diabetes, and an agent for treating an immunodeficiency disorder. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK (e.g., BTK C481S mutant).
Another aspect of the application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, in the manufacture of a medicament for the treatment, prevention, inhibition or elimination of a cell proliferative disorder. In one embodiment, the cell proliferative disorder is cancer.
In another aspect, the present application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, in the manufacture of a medicament for the treatment, prevention, inhibition or elimination of a cell proliferative disorder. In one embodiment, the cell proliferative disorder is cancer.
Another aspect of the application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, in the manufacture of a medicament for modulating BTK. In one embodiment, modulating BTK is inhibiting BTK. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK (e.g., BTK C481S mutant).
In another aspect, the application relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, in the manufacture of a medicament for modulating BTK. In one embodiment, modulating BTK is inhibiting BTK. In some embodiments, the BTK is wild-type BTK. In other embodiments, the BTK is a mutant BTK (e.g., BTK C481S mutant).
In some embodiments of the methods and uses described herein, the cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, renal cancer, bone marrow disorders, lymphoma, hair cell carcinoma, oral anterior chamber carcinoma, nasopharyngeal carcinoma, pharyngeal carcinoma lip cancer, tongue cancer, mouth cancer, small intestine cancer, colorectal cancer, large intestine cancer, rectal cancer, brain and central nervous system cancer, hodgkin's leukemia, bronchi cancer, thyroid cancer, liver and intrahepatic bile duct cancer, hepatocellular cancer, stomach cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney and renal pelvis cancer, bladder cancer, uterine body cancer, cervical cancer, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, chronic Lymphoid Leukemia (CLL), myelogenous leukemia, oral and pharyngeal cancer, non-hodgkin's lymphoma, melanoma, and villous colon adenoma.
In any embodiment of the application, the cancer may be any cancer in any organ, for example a cancer selected from the group consisting of: glioma, thyroid cancer, breast cancer, small cell lung cancer, non-small cell cancer, gastric cancer, colon cancer, gastrointestinal stromal cancer, pancreatic cancer, cholangiocarcinoma, central nervous system cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cancer, anaplastic large cell lymphoma, leukemia, multiple myeloma, mesothelioma, and melanoma, and combinations thereof.
In some embodiments of the methods and uses described herein, the disease or disorder is an immune disorder. In one embodiment, the immune disorder is rheumatoid arthritis.
In some embodiments of the methods and uses described herein, the disease or disorder is systemic and local inflammation, arthritis, immunosuppression-related inflammation, organ transplant rejection, allergy, ulcerative colitis, crohn's disease, dermatitis, asthma, systemic lupus erythematosus, sjogren's syndrome, multiple sclerosis, scleroderma/systemic sclerosis, idiopathic Thrombocytopenic Purpura (ITP), anti-neutrophil cytoplasmic antibodies (ANCA) vasculitis, chronic Obstructive Pulmonary Disease (COPD), psoriasis.
In one embodiment, a method of treating a disease or disorder associated with the modulation of BTK (including immune disorders, cancer, cardiovascular diseases, viral infections, inflammation, metabolic/endocrine dysfunction, and neurological disorders) comprises administering a compound of formula (11) to a patient suffering from at least one of the disease or disorder.
The compounds disclosed herein may be administered in an amount effective to treat or prevent a disorder in a subject and/or to prevent the development thereof.
The compounds of the application may be administered in a therapeutically effective amount in combination therapy with one or more therapeutic agents (pharmaceutical combinations) or modes (e.g., non-drug therapies). For example, synergistic effects may occur with other antiproliferative, anticancer, immunomodulatory or anti-inflammatory substances. In some embodiments, the compound of formula (I) is administered in combination with an additional therapeutic agent selected from the group consisting of an anti-inflammatory agent, an immunomodulating agent, a chemotherapeutic agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, an agent for treating a hematological disorder, an agent for treating diabetes, and an agent for treating an immunodeficiency disorder. In the case of the administration of the compounds of the application in combination with other therapies, the dosage of the co-administered compounds will of course vary depending on the type of combination employed, the particular drug employed, the condition to be treated, and the like.
Combination therapies include the administration of the subject compounds in further combination with other bioactive ingredients (e.g., without limitation, anti-inflammatory agents, immunomodulators, chemotherapeutics, neurotrophic factors, agents for treating cardiovascular diseases, agents for treating liver diseases, antiviral agents, agents for treating blood disorders, agents for treating diabetes and agents for treating immunodeficiency disorders) and non-drug therapies (e.g., without limitation, surgery or radiation therapy). For example, the compounds of the present application may be used in combination with other pharmaceutically active compounds, preferably compounds that enhance the efficacy of the compounds of the present application. The compounds of the application may be administered simultaneously (as a single formulation or separate formulations) or sequentially with another drug therapy or treatment modality. In general, combination therapies contemplate the administration of two or more drugs during a single cycle or course of therapy.
Pharmaceutical composition
The present application also provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, and at least one pharmaceutically acceptable excipient or carrier.
A "pharmaceutical composition" is a formulation containing a compound of the application in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in a bulk (bulk) dosage form or unit dosage form. The unit dosage form is any of a variety of forms including, for example, a capsule, IV bag, tablet, single pump on an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of a disclosed compound or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog, or derivative thereof) in a unit dose composition is an effective amount and varies depending upon the particular treatment involved. Those skilled in the art will appreciate that routine variations in dosages are sometimes required depending on the age and condition of the patient. The dosage will also depend on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for topical or transdermal administration of the compounds of the present application include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is admixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants which may be required.
As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
By "pharmaceutically acceptable excipient" is meant an excipient that can be used to prepare a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes excipients suitable for veterinary use as well as for human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both one such excipient and more than one such excipient.
The pharmaceutical compositions of the present application are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous application may include the following components: sterile diluents, such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents; antimicrobial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediamine tetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for adjusting the permeability, such as sodium chloride or dextrose. The pH can be adjusted with an acid or base (e.g., hydrochloric acid or sodium hydroxide). Parenteral formulations may be packaged in ampules, disposable syringes or multiple dose vials made of glass or plastic.
The compounds or pharmaceutical compositions of the present application may be administered to a subject using a wide variety of well-known methods currently used in chemotherapy treatment. For example, for the treatment of cancer, the compounds of the application may be injected directly into a tumor, into the blood stream or body cavity, or applied orally or through the skin using a patch. The dosage selected should be sufficient to result in an effective treatment, but not so high as to cause unacceptable side effects. It should be preferable to closely monitor the status of the disease condition (e.g., cancer, precancer, etc.) and the health of the patient during and for a reasonable period of time after treatment.
As used herein, the term "therapeutically effective amount" refers to an amount of an agent for treating, alleviating or preventing an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. The effect may be detected by any assay known in the art. The precise effective amount for a subject will depend on the weight, size, and health of the subject; the nature and extent of the pathology; and selecting a therapeutic agent or combination of therapeutic agents for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation within the skill and judgment of the clinician. In one embodiment, the disease or condition is selected from the group consisting of immune disorders, cancer, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction, and neurological disorders. In another embodiment, the disease or condition to be treated is cancer. In another embodiment, the disease or condition to be treated is a cell proliferative disorder.
For any compound, a therapeutically effective amount can be estimated initially in a cell culture assay (e.g., neoplastic cells), or in an animal model (typically rat, mouse, rabbit, dog, or pig). Animal models can also be used to determine the appropriate concentration ranges and routes of administration. Such information may then be used to determine the available dosages and routes of administration in humans. Can be confirmed in cell culture or experimental animal by standard pharmaceutical proceduresDetermining therapeutic/prophylactic efficacy and toxicity, e.g. ED 5 0 (therapeutically effective dose in 50% of population) and LD 5 0 (dose lethal to 50% of the population). The dose ratio between toxic effect and therapeutic effect is the therapeutic index, and it can be expressed as the ratio: LD (laser diode) 50 /ED 50 . Pharmaceutical compositions exhibiting a large therapeutic index are preferred. The dosage may vary within this range depending upon the dosage form employed, the sensitivity of the patient, and the route of administration.
The dosage and administration are adjusted to provide adequate levels of active agent, or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the general health, age, weight and sex of the subject, diet, time and frequency of administration, drug combination, response sensitivity and tolerance/response to therapy. Depending on the half-life and clearance of the particular formulation, the long-acting pharmaceutical composition may be administered every 3 to 4 days, weekly or biweekly.
Pharmaceutical compositions containing the active compounds of the present application (i.e., compounds of formula (I)) can be prepared in generally known manner, for example, by means of conventional mixing, dissolving, granulating, dragee-making, water-borne, emulsifying, encapsulating, entrapping or lyophilizing processes. Conventional methods may be employed to formulate pharmaceutical compositions using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Of course, the appropriate formulation will depend on the route of administration selected.
Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, cremophor EL TM (BASF, parippany, n.j.) or Phosphate Buffered Saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy injectability exists. It must be stable under the conditions of preparation and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or a fraction A dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. Prevention of microbial action can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like). In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols (e.g., mannitol, sorbitol), sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition agents which delay absorption, for example, aluminum monostearate and gelatin.
A sterile injectable solution can be prepared by: the active compound is combined in the desired amount in a suitable solvent with one or a combination of the ingredients listed above, if desired, followed by filter sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation are vacuum drying and freeze-drying which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purposes of oral therapeutic administration, the active compounds may be combined with excipients and used in the form of tablets, troches or capsules. Oral compositions may also be prepared using a fluid carrier for use as a mouthwash, wherein the compounds in the fluid carrier are applied orally, rinsed and expectorated or swallowed. Pharmaceutically compatible binders and/or auxiliary materials may be included as part of the composition. Tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of similar nature: a binder, such as microcrystalline cellulose, gum tragacanth or gelatin; excipients, for example starch or lactose; disintegrants, for example alginic acid, primogel or corn starch; lubricants, such as magnesium stearate or Sterotes; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or a flavouring agent, such as peppermint, methyl salicylate or orange flavouring.
For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser, or nebulizer, containing a suitable propellant (e.g., a gas such as carbon dioxide).
Systemic administration may also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, cleaners, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated as ointments, salves, gels, or creams as generally known in the art.
The active compounds can be prepared using pharmaceutically acceptable carriers that will protect the compound from rapid elimination from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid may be used. Methods of preparing such formulations will be apparent to those skilled in the art. The materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art (e.g., as described in U.S. Pat. No. 4,522,811).
It is particularly advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suitable as unitary dosages for the subject to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the desired pharmaceutical carrier. The specification of the dosage unit form of the application is determined by and directly depends on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.
In therapeutic applications, the dosage of the pharmaceutical composition used according to the present application varies depending on, among other factors affecting the selected dosage, the agent, the age, weight and clinical condition of the patient being treated, and the experience and judgment of the clinician or practitioner administering the therapy. In general, the dose should be sufficient to cause a slowing of the tumor growth and preferably regression, and also preferably cause complete regression of the cancer. The dosage may range from about 0.01 mg/kg/day to about 5000 mg/kg/day. An effective amount of the agent is an amount that provides an objectively identifiable improvement as noted by a clinician or other qualified observer. For example, regression of a tumor in a patient can be measured in relation to tumor diameter. A decrease in tumor diameter indicates regression. Regression is also indicated by the inability of the tumor to reoccur after cessation of treatment. As used herein, the term "dose-effective manner" refers to the amount of active compound that produces a desired biological effect in a subject or cell.
The pharmaceutical composition may be included in a container, package, or dispenser together with instructions for administration.
As used herein, "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present application, wherein the parent compound is modified by preparing an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines), alkali metal or organic salts of acidic residues (e.g., carboxylic acids), and the like. Pharmaceutically acceptable salts include the parent compounds such as conventional non-toxic salts or quaternary ammonium salts formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those obtained from inorganic and organic acids selected from the group consisting of: 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, acid-type carbonic acid, citric acid, ethylenediamine tetraacetic acid, ethane disulfonic acid, 1, 2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, ethylene glycol phenylarsonic acid (glycollyarsanilic acid), hexylresorcinol acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, basic acetic acid, succinic acid, sulfamic acid, sulfanilic acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly occurring amine acids such as glycine, alanine, phenylalanine, arginine, and the like.
Other examples of pharmaceutically acceptable salts include caproic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo- [2.2.2] -oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, muconic acid, and the like. The present application also includes salts formed when acidic protons present in the parent compound are replaced with metal ions, such as alkali metal ions, alkaline earth metal ions, or aluminum ions, or coordinated with organic bases, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
It is to be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystalline forms (polymorphs) of the same salt as defined herein.
The compounds of the application may also be prepared as esters (e.g., pharmaceutically acceptable esters). For example, carboxylic acid functionality in a compound can be converted to its corresponding ester, such as methyl, ethyl, or other esters. Likewise, the alcohol groups in the compounds may be converted to their corresponding esters, such as acetates, propionates or other esters.
The compounds of the application may also be prepared as prodrugs (e.g., pharmaceutically acceptable prodrugs). The terms "pro-drug" and "prodrug" are used interchangeably herein and refer to any compound that releases the active parent drug in vivo. Because prodrugs are known to enhance numerous desirable qualities of drugs (e.g., solubility, bioavailability, preparation, etc.), the compounds of the present application may be delivered in prodrug form. Accordingly, the present application is intended to cover prodrugs of the presently claimed compounds, methods of delivering the prodrugs, and compositions containing the prodrugs. "prodrugs" are intended to include any covalently linked carriers that release the active parent drug of the present application in vivo when such prodrugs are administered to a subject. Prodrugs of the application are prepared by modifying functional groups present in the compound in such a way that the modification cleaves to the parent compound either in routine handling or in vivo. Prodrugs include compounds of the application wherein a hydroxy, amino, mercapto, carboxyl, or carbonyl group is bonded to any group that is cleavable in vivo to form a free hydroxy, free amino, free mercapto, free carboxyl, or free carbonyl group, respectively.
Examples of Prodrugs include, but are not limited to, esters of hydroxy-functional groups (e.g., acetates, dialkylaminoacetates, formates, phosphates, sulfates, and benzoate derivatives) and carbamates (e.g., N-dimethylaminocarbonyl), esters of carboxy-functional groups (e.g., ethyl esters, morpholinoethanate 1, N-acyl derivatives of amino-functional groups (e.g., N-acetyl) N-Mannich bases, schiff bases, and enaminones, oximes, acetals, ketals, and enolates of ketone and aldehyde functional groups, and the like, in the compounds of the present application, see Bundegaard, H.design of Prodrugs, pages 1-92, eleseveler, new York-Oxford (1985).
The compound or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof is administered orally, nasally, transdermally, pulmonary, inhaled, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.
The dosage regimen utilizing the compounds is selected in accordance with a variety of factors, including the type, kind, age, weight, sex and medical condition of the patient; severity of the condition to be treated; route of application; renal and hepatic function in the patient; and the particular compound employed or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof. An average physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
Techniques for formulating and administering the disclosed compounds can be found in Remington: the Science and Practice of Pharmacy, 19 th edition, mack Publishing co., easton, PA (1995). In one embodiment, the compounds described herein, and pharmaceutically acceptable salts, tautomers, prodrugs, solvates, metabolites, polymorphs, analogs, or derivatives thereof, are used in combination with pharmaceutically acceptable carrier or diluent in pharmaceutical formulations. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compound or pharmaceutically acceptable salt, prodrug, solvate, metabolite, polymorph, analog or derivative thereof will be present in such pharmaceutical compositions in an amount sufficient to provide the required dose within the scope described herein.
All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the application will be apparent from the different embodiments. The examples provided illustrate the different components and methods that can be used to practice the present application. The examples do not limit the claimed application. Based on the present application, the skilled artisan can identify and employ other components and methods useful in practicing the present application.
The application also relates to the following embodiments:
1. a compound of formula (I):
or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analogue or derivative thereof.
2. A pharmaceutical composition comprising a compound of embodiment 1 or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, and a pharmaceutically acceptable diluent, excipient or carrier.
3. A method of treating a BTK-mediated disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of embodiment 1, or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, or a pharmaceutical composition of embodiment 2.
4. The method of embodiment 3, wherein the BTK-mediated disorder is selected from the group consisting of an immune disorder, cancer, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction, and neurological disorder.
5. The method according to the embodiment 4, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular cancer, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, renal cancer, pancreatic cancer, bone marrow disorders, lymphoma, hair cell carcinoma, anterior chamber carcinoma, nasopharyngeal carcinoma, pharyngeal carcinoma lip cancer, tongue cancer, mouth cancer, small intestine cancer, colorectal cancer, large intestine cancer, rectal cancer, brain and central nervous system cancer, hodgkin's leukemia, bronchi cancer, thyroid cancer, liver and intrahepatic bile duct cancer, hepatocellular cancer, stomach cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney and renal pelvis cancer, bladder cancer, uterine body cancer, cervical cancer, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, chronic Lymphoid Leukemia (CLL), myelogenous leukemia, oral and pharyngeal cancer, non-hodgkin's lymphoma, melanoma, and villous colon adenoma.
6. The method of embodiment 4, wherein the disorder is rheumatoid arthritis, systemic and local inflammation, arthritis, immunosuppression-related inflammation, organ transplant rejection, allergy, ulcerative colitis, crohn's disease, dermatitis, asthma, systemic lupus erythematosus, galenic syndrome, multiple sclerosis, scleroderma/systemic sclerosis, idiopathic Thrombocytopenic Purpura (ITP), anti-neutrophil cytoplasmic antibodies (ANCA) vasculitis, chronic Obstructive Pulmonary Disease (COPD), or psoriasis.
7. A method of modulating BTK comprising administering to a patient in need thereof an effective amount of a compound of embodiment 1 or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, or a pharmaceutical composition of embodiment 2.
8. A compound of embodiment 1 or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, or a pharmaceutical composition of embodiment 2, for use in a method of treating a BTK-mediated disorder or modulating BTK.
9. The compound or composition of embodiment 8, wherein the BTK-mediated disorder is selected from the group consisting of an immune disorder, cancer, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction, and neurological disorder.
10. The compound or composition of embodiment 9, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular cancer, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, renal cancer, pancreatic cancer, bone marrow disorders, lymphoma, hair cell carcinoma, anterior chamber carcinoma, nasopharyngeal carcinoma, pharyngeal carcinoma lip cancer, tongue cancer, mouth cancer, small intestine cancer, colorectal cancer, large intestine cancer, rectal cancer, brain and central nervous system cancer, hodgkin's leukemia, bronchi cancer, thyroid cancer, liver and intrahepatic bile duct cancer, hepatocellular cancer, stomach cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney and renal pelvis cancer, bladder cancer, uterine body cancer, cervical cancer, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, chronic Lymphoid Leukemia (CLL), myelogenous leukemia, oral and pharyngeal cancer, non-hodgkin's lymphoma, melanoma, and villous colon adenoma.
11. A compound or composition of embodiment 9 wherein the condition is rheumatoid arthritis, systemic and local inflammation, arthritis, immunosuppression-related inflammation, organ transplant rejection, allergy, ulcerative colitis, crohn's disease, dermatitis, asthma, systemic lupus erythematosus, sjogren's syndrome, multiple sclerosis, scleroderma/systemic sclerosis, idiopathic Thrombocytopenic Purpura (ITP), anti-neutrophil cytoplasmic antibody (ANCA) vasculitis, chronic Obstructive Pulmonary Disease (COPD), or psoriasis.
12. Use of a compound of embodiment 1 or a pharmaceutically acceptable salt, tautomer, prodrug, solvate, metabolite, polymorph, analog or derivative thereof, or a pharmaceutical composition of embodiment 2, in the manufacture of a medicament for treating a BTK-mediated disorder or for modulating BTK.
13. The use of embodiment 12, wherein the BTK-mediated disease or disorder is selected from the group consisting of an immune disorder, cancer, cardiovascular disease, viral infection, inflammation, metabolic/endocrine dysfunction, and neurological disorder.
14. The use according to the embodiment 13, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular cancer, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, renal cancer, pancreatic cancer, bone marrow disorders, lymphoma, hair cell carcinoma, anterior chamber carcinoma, nasopharyngeal carcinoma, pharyngeal carcinoma lip cancer, tongue cancer, mouth cancer, small intestine cancer, colorectal cancer, large intestine cancer, rectal cancer, brain and central nervous system cancer, hodgkin's leukemia, bronchi cancer, thyroid cancer, liver and intrahepatic bile duct cancer, hepatocellular cancer, stomach cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney and renal pelvis cancer, bladder cancer, uterine body cancer, cervical cancer, multiple myeloma, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, chronic Lymphoid Leukemia (CLL), myelogenous leukemia, oral and pharyngeal cancer, non-hodgkin's lymphoma, melanoma, and villous colon adenoma.
15. The use of embodiment 13, wherein the disorder is rheumatoid arthritis, systemic and local inflammation, arthritis, immunosuppression-related inflammation, organ transplant rejection, allergy, ulcerative colitis, crohn's disease, dermatitis, asthma, systemic lupus erythematosus, sjogren's syndrome, multiple sclerosis, scleroderma/systemic sclerosis, idiopathic Thrombocytopenic Purpura (ITP), anti-neutrophil cytoplasmic antibodies (ANCA) vasculitis, chronic Obstructive Pulmonary Disease (COPD), or psoriasis.
Detailed Description
Examples
The present application is further illustrated by the following examples and synthetic schemes which are not to be construed as limiting the scope or spirit of the application to the specific steps described herein. It should be understood that the examples are provided to illustrate certain embodiments and are thus not intended to limit the scope of the application. It is further understood that various other embodiments, modifications, and equivalents thereof may be resorted to, and that may be apparent to those skilled in the art without departing from the spirit of this application and/or the scope of the appended claims.
Analytical methods, materials and apparatus
Unless otherwise indicated, reagents and solvents were used as received from suppliers. Proton Nuclear Magnetic Resonance (NMR) spectra were obtained from 400MHz Bruker or Varian spectrometers. The profile is given in ppm (delta) and the coupling constant J is reported in hertz. Tetramethylsilane (TMS) was used as an internal standard. Mass spectra were collected using a Waters ZQ single quadrupole mass spectrometer (ion trap ESI). Purity and low resolution mass spectral data were measured using a Waters acquisition i-stage ultra-high performance liquid chromatography (UPLC) system with an acquisition photodiode array detector, an acquisition Evaporative Light Scattering Detector (ELSD), and a Waters ZQ mass spectrometer. Data were obtained using Waters MassLynx 4.1 software and purity was characterized by UV wavelength 220nm, ELSD and ESI. Column: acquity UPLC BEH C18.1.7 μm 2.1X50mm; flow rate: 0.6mL/min; solvent A (95/5/0.1 10mM ammonium formate/acetonitrile/formic acid), solvent B (95/5/0.09 acetonitrile/water/formic acid); gradient: 0-2min:5-100% B, 100% B to 2.2min followed by 5% B at 2.21 min.
Abbreviations used in the following examples and elsewhere herein are:
DCM dichloromethane
DIEA N, N-diisopropylethylamine
DIPEA N, N-diisopropylethylamine
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
DTT dithiothreitol
EDTA ethylenediamine tetraacetic acid
EGTA ethylene glycol tetraacetic acid
Et 2 O-diethyl ether
EtOAc ethyl acetate
EtOH ethanol
LCMS liquid chromatography-mass spectrometry
MeOH methanol
MS mass spectrometry
NMR nuclear magnetic resonance
ppm parts per million
Example 1: 2-chloro-4-phenoxybenzoate (intermediate 2-D)
Step 1:2-chloro-4-phenoxybenzonitrile (intermediate 2-B)
Phenol (3.66 g,39 mmol) dissolved in DMF (30 mL) was treated in small portions with NaH 60% (1.56 g,39 mmol) dispersed in oil until gas evolution ceased. The reaction mixture was stirred at room temperature for 10 minutes, followed by the addition of 2-chloro-4-fluorobenzonitrile (2-A, 5.0g,32.5 mmol). The mixture was stirred at room temperature for 3 hours until completion (LCMS). Volatiles were removed under vacuum and the crude product was partitioned in DCM/water. The organic phase was separated and washed with saturated brine solution, and dried over Na 2 SO 4 And (5) drying. Concentration gave 7.5g of an off-white solid. 1 H NMR(400MHz，DMSO-d 6 )d 7.96(d，J＝8.7Hz，1H)，7.51(t，J＝7.9Hz，2H)，7.33(d，J＝7.4Hz，1H)，7.30(d，J＝2.3Hz，1H)，7.20(d，J＝7.9Hz，2H)，7.04(dd，J＝8.7，2.3Hz，1H)；MSm/z 230[M+H] + 。
Step 2: 2-chloro-4-phenoxybenzoic acid (intermediate 2-C)
2-chloro-4-phenoxybenzonitrile (2-B, 7.0g,30.6 mmol), potassium hydroxide 5M (100 mL) and EtOH (20 mL) were stirred at reflux for 6 hours (until the starting material was consumed). The mixture was cooled to room temperature and the mixture was slowly acidified with concentrated HCl. The precipitate was filtered off and dried to give an off-white solid (2-C, 7.15g, 94%). NMR (400 MHz, DMSO-d) 6 )d13.22(s，1H)，7.88(d，J＝8.7Hz，1H)，7.48(t，J＝7.8Hz，2H)，7.27(t，J＝7.4Hz，1H)，7.16(d，J＝8.0Hz，2H)，7.08(d，J＝2.2Hz，1H)，6.97(dd，J＝8.7，2.3Hz，1H)；MS m/z 249[M+H] + 。
Step 3: 2-chloro-4-phenoxybenzoic acid methyl ester (intermediate 2-D)
By reacting 2-chloro-4-Phenoxybenzoic acid (2-C, 5.0g,20.2 mmol) was dissolved in DMF (50 mL) and solid K was added 2 CO 3 (4.15 g,30.1 mmol). The reaction mixture was cooled to 0deg.C and methyl iodide (14 mL,22.2 mmol) was added dropwise. The mixture was allowed to warm to room temperature over 1 hour. During which the starting material is totally consumed. The mixture was diluted with water and treated with Et 2 And O extraction. Drying under vacuum and concentration gave a yellow oil (2-D, 4.15g, 79%) which was used without further purification. NMR (400 MHz, DMSO-d) 6 )d 7.89(d，J＝8.7Hz，1H)，7.49(t，J＝7.9Hz，2H)，7.29(t，J＝7.4Hz，1H)，7.17(d，J＝7.9Hz，2H)，7.12(d，J＝2.4Hz，1H)，6.99(dd，J＝8.7，2.4Hz，1H)，3.84(s，3H)；MSm/z 263[M+H] + 。
Example 2: (2-chloro-4-phenoxyphenyl) (4- (((3R, 6S) -6- (hydroxymethyl) tetrahydro-2H-pyran-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (compound (I))
Step 1: 5-bromo-4-chloro-7H-pyrrolo [2,3-d ] pyrimidine (intermediate 2-F)
4-chloro-7H-pyrrolo [2,3-d ] dissolved in DCM (800 mL) was treated in portions with N-bromosuccinimide (26.7 g,149.8 mmol)]Pyrimidine (2-E, 20.0g,130.7 mmol) while maintaining a temperature of about 25-30 ℃. The reaction mixture was stirred at room temperature overnight. Water (500 mL) was added and the phases were separated. The organic phase was taken up in Na 2 SO 4 Dried, filtered and concentrated in vacuo. The crude product was taken up in Et 2 O was triturated and filtered to give 5-bromo-4-chloro-7H-pyrrolo [2,3-d ] as a white solid]Pyrimidine (2-F, 22.43g, 74%). Melting point: 242-244 ℃; 1 H NMR(400MHz，DMSO-d 6 )d 12.96(s，1H)，8.61(s，1H)，7.94(s，1H)；MS m/z 232[M( 35 Cl， 79 Bt)+H] + ，234[M( 35 Cl， 81 Br)+H] + ，234[M( 37 Cl， 79 Br)+H] + ，236[M( 37 Cl， 81 Br)+H] + 。
step 2: (2-chloro-4-phenoxyphenyl) (4-chloro-7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (intermediate 2-G)
5-bromo-4-chloro-7H-pyrrolo [2,3-d ] in THF (200 mL) at-78deg.C under an inert atmosphere]To a stirred solution of pyrimidine (2-F, 6.90g,29.7 mmol) was added n-BuLi (2.69M in hexane, 23.2mL,62.3 mmol) dropwise. The reaction mixture was held at-78 ℃ for 1 hour, and then a solution of precooled (to-78 ℃) methyl 2-chloro-4-phenoxybenzoate (2-D, 8.19g,31.2 mmol) in THF (80 mL) was added. The reaction mixture was stirred at-78 ℃ for 1 hour and then quenched by the addition of HCl 1N (65 mL). The mixture was allowed to warm to room temperature and then extracted with EtOAc (3X 100 mL). The combined extracts were washed with brine, over Na 2 SO 4 Dried and concentrated under vacuum. By column chromatography (SiO 2 hexane/EtOAc) to give (2-chloro-4-phenoxyphenyl) (4-chloro-7H-pyrrolo [2, 3-d) as a white solid]Pyrimidin-5-yl) methanone (2-G, 4.73G, 41%). 1 H NMR(400MHz，DMSO-d 6 )d 13.426(s，1H)，8.75(s，1H)，8.14(s，1H)，7.60(d，J＝8.5Hz，1H)，7.49(t，J＝7.9Hz，2H)，7.26(t，J＝7.4Hz，1H)，7.23-7.12(m，3H)，7.01(dd，J＝8.5，2.3Hz，1H)；MS m/z 384[M( 35 Cl， 35 Cl)+H] + ，386[M( 35 Cl， 37 Cl)+H] + ，388[M( 37 Cl， 37 Cl)+H] + 。
Step 3: (2-chloro-4-phenoxyphenyl) (4. (((3R, 6S) -6- (hydroxymethyl) tetrahydro-2H-pyran-3-yl) amino) -7H-pyrrolo [2,3-d ] pyrimidin-5-yl) methanone (I)
(2-chloro-4-phenoxyphenyl) (4-chloro-7H-pyrrolo [2, 3-d)]A mixture of pyrimidin-5-yl) methanone (2-G, 200mg,0.52 mmol), ((2S, 5R) -5-aminotetrahydro-2H-pyran-2-yl) methanol (72 mg,0.54 mmol) and DIPEA (272 mL,1.56 mmol) was stirred at 160℃for 1 hour under microwave irradiation. Volatiles were removed under vacuum and purified by column chromatography (NH 2 -SiO 2 The residue was purified with DCM/MeOH to give (2-chloro-4-phenoxyphenyl) (4- (((3R, 6S) -6- (hydroxymethyl) tetrahydro-2H-pyran-3-yl) amino) as an off-white solid-7H-pyrrolo [2,3-d]Pyrimidin-5-yl) methanone ((I), 175mg, 70%). 1 H NMR(400MHz，DMSO-d 6 )d 12.76(s，1H)，8.60(d，J＝7.1Hz，1H)，8.25(s，1H)，7.64(s，1H)，7.58(d，J＝8.4Hz，1H)，7.48(t，J＝7.6Hz，2H)，7.26(t，J＝7.2Hz，1H)，7.18-7.20(m，3H)，7.02(d，J＝8.3Hz，1H)，4.67(s，1H)，4.16(d，J＝7.7Hz，2H)，3.49-3.27(m，3H)，3.12(t，J＝11.2Hz，1H)，2.19(d，J＝11.4Hz，1H)，1.78(d，J＝12.9Hz，1H)，1.67-1.49(m，1H)，1.39(d，J＝12.3Hz，1H)；MS m/z 479[M( 35 Cl)+H] + ，481[M( 37 Cl)+H] + 。
Example 3: determination of BTK kinase Activity
Test inhibitors and controls (CGI-1746, GDC-0834, PCI-32765, dasatinib and R-406) were prepared in 10% DMSO at 10 times the desired final concentration and added to each well of a reaction plate (Corning 96-well half-solid white unbound surface plate) in a volume of 2.5. Mu.L. Full-length active BTK was diluted in assay buffer (50mM Tris,pH 8.0,0.02mg/mL BSA,10mM MgCl) 2 1mM EGTA,10% glycerol, 0.2mM Na 3 VO 4 1mM DTT,0.1mM beta-glycerophosphate and 0.2mM NaF) and 17.5. Mu.L volume was added to each well for a final concentration of 0.08nM in the 25. Mu.L reaction. After a pre-incubation of 30 minutes at room temperature, the kinase reaction was initiated by adding 5 μl of an activation mixture diluted in assay buffer containing biotinylated plcγ2 peptide and ATP to reach a final concentration of 150nM biotinylated plcγ2 and 180 μΜ ATP. Plates were incubated for 60 minutes at room temperature. The reaction was stopped in the dark by adding 10. Mu.L of a stop/detect mixture containing EDTA and alpha Screen TM Streptavidin donor and anti-pTYR 100 acceptor beads in assay buffer. EDTA final concentration of 10mM, alpha Screen TM The final concentration of both donor and acceptor beads was 500 ng/well. The assay plates were incubated at room temperature in the dark for 60 minutes and read on a Perkin Elmer Envision Multilabel plate reader (excitation wavelength: 640nm, emission wavelength: 570 nm). The results are shown in table 1.
Example 4: determination of BTK C481S kinase Activity
Test inhibitors and controls (staurosporine) were prepared in 10% dmso at 10 times the desired final concentration and added to each well of a reaction plate (Corning 96-well half-face solid white unbound surface plate) in a volume of 2.5 μl. Full length BTKC481S was diluted in assay buffer (50mM Tris,pH 8.0,0.02mg/ml BSA,10mM MgCl) 2 1mM MEGTA,10% glycerol, 1mM DTT,0.1mM beta-glycerophosphate and 1mM NaF) and 17.5. Mu.L volumes were added to each well for a final concentration of 10nM in 25. Mu.L reaction. After a pre-incubation of 30 minutes at room temperature, the kinase reaction was initiated by adding 5 μl of an activation mixture diluted in assay buffer containing biotinylated plcγ2 peptide and ATP to reach final concentrations of 125nM biotinylated plcγ2 and 60 μΜ ATP. Plates were incubated for 60 minutes at room temperature. The reaction was stopped in the dark by adding 10. Mu.l of a stop/detect mixture containing EDTA, staurosporine and AlphaScreen TM Streptavidin donor and anti-pTYR 100 acceptor beads in assay buffer. EDTA final concentration of 15mM, staurosporine final concentration of 1. Mu.M, alpha Screen TM (amplified chemiluminescent affinity homogeneous assay) technique the final concentration of both donor and acceptor beads was 500 ng/well. The assay plates were incubated at room temperature in the dark for 60 minutes and read on a Perkin Elmer Envision Multilabel plate reader (excitation wavelength: 640nm, emission wavelength: 570 nm). The results are shown in table 1.
Example 5: antiproliferative assays
Cell viability was determined by the MTS assay. Briefly, cells (i.e., TMD-8 cells or Rec-1 cells) were plated at 2,000-10,000 cells/well on 9-well plates, cultured in complete growth medium for 24 hours, and then treated with various drugs and drug combinations for 72 hours. MTS/PMS was added and incubated for 4 hours, followed by assessment of cell viability using a microplate reader (absorbance at 490 nm). Data were normalized to untreated controls and analyzed with Microsoft Excel. The results are shown in table 1.
Table 1: biological Activity of Compound (I)
Equivalent solution
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed by the scope of the following claims.

Claims (19)

1. Use of a pharmaceutical composition for the manufacture of a medicament for treating cancer in a subject in need thereof, wherein the pharmaceutical composition comprises a compound of formula (I):
or a pharmaceutically acceptable salt, or tautomer thereof, wherein the cancer is a mutant BTK-mediated cancer.
2. The use of claim 1, wherein the mutant BTK comprises a drug resistance mutation.
3. The use of claim 2, wherein the drug resistance mutation is a mutation at amino acid 481.
4. The use of claim 2, wherein the drug resistance mutation is C481S.
5. The use of claim 1, wherein the cancer is resistant to BTK inhibitors.
6. The use of claim 5, wherein the BTK inhibitor is ibrutinib.
7. The use of claim 1, wherein the cancer is selected from ovarian cancer, cervical cancer, testicular cancer, esophageal cancer, gastric cancer, skin cancer, lung cancer, bone cancer, colon cancer, biliary tract cancer, hair cell cancer, oral anterior chamber cancer, nasopharyngeal cancer, oral cancer, colorectal cancer, small intestine cancer, rectal cancer, brain and central nervous system cancer, bronchial cancer, liver cancer, intrahepatic bile duct cancer, bladder cancer, uterine body cancer, renal pelvis cancer, oral cancer, pharyngeal cancer, neuroblastoma, keratoacanthoma, squamous cell carcinoma, large cell carcinoma, small cell carcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, renal cancer, myelopathy, lymphoma, hodgkin's leukemia, glioma, endometrial cancer, multiple myeloma, lymphoblastic leukemia, and myelogenous leukemia.
8. The use of claim 1, wherein the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), adenocarcinoma, villous colon adenoma, lip cancer, tongue cancer, colorectal cancer, laryngeal cancer, chronic Lymphoid Leukemia (CLL), non-hodgkin's lymphoma, hepatocellular carcinoma, glioblastoma, acute myelogenous leukemia, and chronic myelogenous leukemia.
9. The use of claim 1, wherein the cancer is selected from lung adenocarcinoma, breast cancer, prostate cancer, pancreatic cancer, and thyroid cancer.
10. The use of claim 1, wherein the cancer is chronic lymphoid leukemia.
11. The use of claim 1, wherein the cancer is lymphoma.
12. The use of claim 11, wherein the lymphoma is non-hodgkin's lymphoma.
13. The use of claim 11, wherein the lymphoma is a B-cell lymphoma.
14. The use of claim 11, wherein the lymphoma is anaplastic large cell lymphoma, central Nervous System (CNS) lymphoma, or waldenstrom's macroglobulinemia.
15. The use of claim 1, wherein the cancer is a bone marrow disorder or myelogenous leukemia.
16. The use of claim 1, wherein the cancer is acute myeloid leukemia.
17. The use of claim 1, wherein the cancer is multiple myeloma.
18. The use of claim 1, wherein the cancer is lymphoblastic leukemia.
19. The use of claim 1, wherein the cancer is a sarcoma or brain tumor.
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